SUMMARY Project 3: iPSC-CM Screening to Discover Mechanisms and Therapeutic Targets Heart failure (HF) is major cause of morbidity and mortality worldwide and affects 1?2% of the US population and represents a major public health burden. Heart failure patients are particularly sensitive to arrhythmia. Up to 50% of HF patients die from arrhythmias and sudden cardiac death, creating a precarious health risk, yet few drugs are effective in this population. Project 3 of this PPG addresses two major questions relevant to the clinical management of these patients: 1) Why are HF patients particularly susceptible to drug-induced arrhythmia (Aim 1) and 2) Can we discover proteins that can be targeted pharmaceutically to create entirely new classes of drugs to treat arrhythmia in these patients (Aims 2 and 3)? We will use iPSC-derived cardiomyocytes from dilated cardiomyopathy (DCM) patients (Project 1 and CRISPR genome editing) as the first step to study mechanisms at the protein and signaling level and to identify candidate drug targets. To date, physiological screening of cardiomyocytes has lacked the throughput and prediction accuracy needed to systematically probe mechanisms and discover therapeutic targets. Project 3 will use instrument and iPSC-cardiomyocyte technology we developed over the last decade to overcome this limitation. The conclusions that will be drawn from iPSC- cardiomyocytes about mechanisms and candidate drug targets will be evaluated in lower throughput adult cardiomyocyte preparations (within Projects 1 and 2) and in multiscale computational modeling (with Core B) to confirm and extend hypotheses, thereby generating new insight relevant to the intact human heart. Our team, within the Project and PPG, is highly synergistic and uniquely appropriate to carry out this large-scale project that should yield translationally actionable insights to ultimately improve patient management and create safer, more effective therapeutics.